Common variants at SCN5A-SCN10A and HEY2 are associated with Brugada syndrome, a rare disease with high risk of sudden cardiac death

Connie Bezzina; Julien Barc; Yuka Mizusawa; Carol Ann Remme; Jean-Baptiste Gourraud; Floriane Simonet; Arie O Verkerk; Peter J Schwartz; Lia Crotti; Federica Dagradi; Pascale Guicheney; Véronique Fressart; Antoine Leenhardt; Charles Antzelevitch; Susan Bartkowiak; Martin Borggrefe; Rainer Schimpf; Eric Schulze-Bahr; Sven Zumhagen; Elijah R Behr; Rachel Bastiaenen; Jacob Tfelt-Hansen; Morten Salling Olesen; Stefan Kääb; Britt M Beckmann; Peter Weeke; Hiroshi Watanabe; Naoto Endo; Tohru Minamino; Minoru Horie; Seiko Ohno; Kanae Hasegawa; Naomasa Makita; Akihiko Nogami; Wataru Shimizu; Takeshi Aiba; Philippe Froguel; Beverley Balkau; Olivier Lantieri; Margherita Torchio; Cornelia Wiese; David Weber; Rianne Wolswinkel; Ruben Coronel; Bas J Boukens; Stéphane Bézieau; Eric Charpentier; Stéphanie Chatel; Aurore Despres; Françoise Gros; Florence Kyndt; Simon Lecointe; Pierre Lindenbaum; Vincent Portero; Jade Violleau; Manfred Gessler; Hanno L Tan; Dan M Roden; Vincent M Christoffels; Hervé Le Marec; Arthur A Wilde; Vincent Probst; Jean-Jacques Schott; Christian Dina; Richard Redon

doi:10.1038/ng.2712

Common variants at SCN5A-SCN10A and HEY2 are associated with Brugada syndrome, a rare disease with high risk of sudden cardiac death

Connie Bezzina, Julien Barc, Yuka Mizusawa, Carol Ann Remme, Jean-Baptiste Gourraud, Floriane Simonet, Arie O Verkerk, Peter J Schwartz, Lia Crotti, Federica Dagradi, Pascale Guicheney, Véronique Fressart, Antoine Leenhardt, Charles Antzelevitch, Susan Bartkowiak, Martin Borggrefe, Rainer Schimpf, Eric Schulze-Bahr, Sven Zumhagen, Elijah R BehrRachel Bastiaenen, Jacob Tfelt-Hansen, Morten Salling Olesen, Stefan Kääb, Britt M Beckmann, Peter Weeke, Hiroshi Watanabe, Naoto Endo, Tohru Minamino, Minoru Horie, Seiko Ohno, Kanae Hasegawa, Naomasa Makita, Akihiko Nogami, Wataru Shimizu, Takeshi Aiba, Philippe Froguel, Beverley Balkau, Olivier Lantieri, Margherita Torchio, Cornelia Wiese, David Weber, Rianne Wolswinkel, Ruben Coronel, Bas J Boukens, Stéphane Bézieau, Eric Charpentier, Stéphanie Chatel, Aurore Despres, Françoise Gros, Florence Kyndt, Simon Lecointe, Pierre Lindenbaum, Vincent Portero, Jade Violleau, Manfred Gessler, Hanno L Tan, Dan M Roden, Vincent M Christoffels, Hervé Le Marec, Arthur A Wilde, Vincent Probst, Jean-Jacques Schott, Christian Dina, Richard Redon

Molecular Cardiology and Membrane Proteins

313 Citations (Scopus)

Abstract

Brugada syndrome is a rare cardiac arrhythmia disorder, causally related to SCN5A mutations in around 20% of cases. Through a genome-wide association study of 312 individuals with Brugada syndrome and 1,115 controls, we detected 2 significant association signals at the SCN10A locus (rs10428132) and near the HEY2 gene (rs9388451). Independent replication confirmed both signals (meta-analyses: rs10428132, P = 1.0 × 10 -68; rs9388451, P = 5.1 × 10 -17) and identified one additional signal in SCN5A (at 3p21; rs11708996, P = 1.0 × 10 -14). The cumulative effect of the three loci on disease susceptibility was unexpectedly large (P trend = 6.1 × 10 -81). The association signals at SCN5A-SCN10A demonstrate that genetic polymorphisms modulating cardiac conduction can also influence susceptibility to cardiac arrhythmia. The implication of association with HEY2, supported by new evidence that Hey2 regulates cardiac electrical activity, shows that Brugada syndrome may originate from altered transcriptional programming during cardiac development. Altogether, our findings indicate that common genetic variation can have a strong impact on the predisposition to rare diseases.

Original language	English
Journal	Nature Genetics
Volume	45
Issue number	9
Pages (from-to)	1044-1049
Number of pages	6
ISSN	1061-4036
DOIs	https://doi.org/10.1038/ng.2712
Publication status	Published - Sept 2013

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Bezzina, C., Barc, J., Mizusawa, Y., Remme, C. A., Gourraud, J-B., Simonet, F., Verkerk, A. O., Schwartz, P. J., Crotti, L., Dagradi, F., Guicheney, P., Fressart, V., Leenhardt, A., Antzelevitch, C., Bartkowiak, S., Borggrefe, M., Schimpf, R., Schulze-Bahr, E., Zumhagen, S., ... Redon, R. (2013). Common variants at SCN5A-SCN10A and HEY2 are associated with Brugada syndrome, a rare disease with high risk of sudden cardiac death. Nature Genetics, 45(9), 1044-1049. https://doi.org/10.1038/ng.2712

Bezzina, C, Barc, J, Mizusawa, Y, Remme, CA, Gourraud, J-B, Simonet, F, Verkerk, AO, Schwartz, PJ, Crotti, L, Dagradi, F, Guicheney, P, Fressart, V, Leenhardt, A, Antzelevitch, C, Bartkowiak, S, Borggrefe, M, Schimpf, R, Schulze-Bahr, E, Zumhagen, S, Behr, ER, Bastiaenen, R, Tfelt-Hansen, J, Olesen, MS, Kääb, S, Beckmann, BM, Weeke, P, Watanabe, H, Endo, N, Minamino, T, Horie, M, Ohno, S, Hasegawa, K, Makita, N, Nogami, A, Shimizu, W, Aiba, T, Froguel, P, Balkau, B, Lantieri, O, Torchio, M, Wiese, C, Weber, D, Wolswinkel, R, Coronel, R, Boukens, BJ, Bézieau, S, Charpentier, E, Chatel, S, Despres, A, Gros, F, Kyndt, F, Lecointe, S, Lindenbaum, P, Portero, V, Violleau, J, Gessler, M, Tan, HL, Roden, DM, Christoffels, VM, Le Marec, H, Wilde, AA, Probst, V, Schott, J-J, Dina, C & Redon, R 2013, 'Common variants at SCN5A-SCN10A and HEY2 are associated with Brugada syndrome, a rare disease with high risk of sudden cardiac death', Nature Genetics, vol. 45, no. 9, pp. 1044-1049. https://doi.org/10.1038/ng.2712

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title = "Common variants at SCN5A-SCN10A and HEY2 are associated with Brugada syndrome, a rare disease with high risk of sudden cardiac death",

abstract = "Brugada syndrome is a rare cardiac arrhythmia disorder, causally related to SCN5A mutations in around 20% of cases. Through a genome-wide association study of 312 individuals with Brugada syndrome and 1,115 controls, we detected 2 significant association signals at the SCN10A locus (rs10428132) and near the HEY2 gene (rs9388451). Independent replication confirmed both signals (meta-analyses: rs10428132, P = 1.0 × 10 -68; rs9388451, P = 5.1 × 10 -17) and identified one additional signal in SCN5A (at 3p21; rs11708996, P = 1.0 × 10 -14). The cumulative effect of the three loci on disease susceptibility was unexpectedly large (P trend = 6.1 × 10 -81). The association signals at SCN5A-SCN10A demonstrate that genetic polymorphisms modulating cardiac conduction can also influence susceptibility to cardiac arrhythmia. The implication of association with HEY2, supported by new evidence that Hey2 regulates cardiac electrical activity, shows that Brugada syndrome may originate from altered transcriptional programming during cardiac development. Altogether, our findings indicate that common genetic variation can have a strong impact on the predisposition to rare diseases.",

author = "Connie Bezzina and Julien Barc and Yuka Mizusawa and Remme, {Carol Ann} and Jean-Baptiste Gourraud and Floriane Simonet and Verkerk, {Arie O} and Schwartz, {Peter J} and Lia Crotti and Federica Dagradi and Pascale Guicheney and V{\'e}ronique Fressart and Antoine Leenhardt and Charles Antzelevitch and Susan Bartkowiak and Martin Borggrefe and Rainer Schimpf and Eric Schulze-Bahr and Sven Zumhagen and Behr, {Elijah R} and Rachel Bastiaenen and Jacob Tfelt-Hansen and Olesen, {Morten Salling} and Stefan K{\"a}{\"a}b and Beckmann, {Britt M} and Peter Weeke and Hiroshi Watanabe and Naoto Endo and Tohru Minamino and Minoru Horie and Seiko Ohno and Kanae Hasegawa and Naomasa Makita and Akihiko Nogami and Wataru Shimizu and Takeshi Aiba and Philippe Froguel and Beverley Balkau and Olivier Lantieri and Margherita Torchio and Cornelia Wiese and David Weber and Rianne Wolswinkel and Ruben Coronel and Boukens, {Bas J} and St{\'e}phane B{\'e}zieau and Eric Charpentier and St{\'e}phanie Chatel and Aurore Despres and Fran{\c c}oise Gros and Florence Kyndt and Simon Lecointe and Pierre Lindenbaum and Vincent Portero and Jade Violleau and Manfred Gessler and Tan, {Hanno L} and Roden, {Dan M} and Christoffels, {Vincent M} and {Le Marec}, Herv{\'e} and Wilde, {Arthur A} and Vincent Probst and Jean-Jacques Schott and Christian Dina and Richard Redon",

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T1 - Common variants at SCN5A-SCN10A and HEY2 are associated with Brugada syndrome, a rare disease with high risk of sudden cardiac death

AU - Bezzina, Connie

AU - Barc, Julien

AU - Mizusawa, Yuka

AU - Remme, Carol Ann

AU - Gourraud, Jean-Baptiste

AU - Simonet, Floriane

AU - Verkerk, Arie O

AU - Schwartz, Peter J

AU - Crotti, Lia

AU - Dagradi, Federica

AU - Guicheney, Pascale

AU - Fressart, Véronique

AU - Leenhardt, Antoine

AU - Antzelevitch, Charles

AU - Bartkowiak, Susan

AU - Borggrefe, Martin

AU - Schimpf, Rainer

AU - Schulze-Bahr, Eric

AU - Zumhagen, Sven

AU - Behr, Elijah R

AU - Bastiaenen, Rachel

AU - Tfelt-Hansen, Jacob

AU - Olesen, Morten Salling

AU - Kääb, Stefan

AU - Beckmann, Britt M

AU - Weeke, Peter

AU - Watanabe, Hiroshi

AU - Endo, Naoto

AU - Minamino, Tohru

AU - Horie, Minoru

AU - Ohno, Seiko

AU - Hasegawa, Kanae

AU - Makita, Naomasa

AU - Nogami, Akihiko

AU - Shimizu, Wataru

AU - Aiba, Takeshi

AU - Froguel, Philippe

AU - Balkau, Beverley

AU - Lantieri, Olivier

AU - Torchio, Margherita

AU - Wiese, Cornelia

AU - Weber, David

AU - Wolswinkel, Rianne

AU - Coronel, Ruben

AU - Boukens, Bas J

AU - Bézieau, Stéphane

AU - Charpentier, Eric

AU - Chatel, Stéphanie

AU - Despres, Aurore

AU - Gros, Françoise

AU - Kyndt, Florence

AU - Lecointe, Simon

AU - Lindenbaum, Pierre

AU - Portero, Vincent

AU - Violleau, Jade

AU - Gessler, Manfred

AU - Tan, Hanno L

AU - Roden, Dan M

AU - Christoffels, Vincent M

AU - Le Marec, Hervé

AU - Wilde, Arthur A

AU - Probst, Vincent

AU - Schott, Jean-Jacques

AU - Dina, Christian

AU - Redon, Richard

PY - 2013/9

Y1 - 2013/9

N2 - Brugada syndrome is a rare cardiac arrhythmia disorder, causally related to SCN5A mutations in around 20% of cases. Through a genome-wide association study of 312 individuals with Brugada syndrome and 1,115 controls, we detected 2 significant association signals at the SCN10A locus (rs10428132) and near the HEY2 gene (rs9388451). Independent replication confirmed both signals (meta-analyses: rs10428132, P = 1.0 × 10 -68; rs9388451, P = 5.1 × 10 -17) and identified one additional signal in SCN5A (at 3p21; rs11708996, P = 1.0 × 10 -14). The cumulative effect of the three loci on disease susceptibility was unexpectedly large (P trend = 6.1 × 10 -81). The association signals at SCN5A-SCN10A demonstrate that genetic polymorphisms modulating cardiac conduction can also influence susceptibility to cardiac arrhythmia. The implication of association with HEY2, supported by new evidence that Hey2 regulates cardiac electrical activity, shows that Brugada syndrome may originate from altered transcriptional programming during cardiac development. Altogether, our findings indicate that common genetic variation can have a strong impact on the predisposition to rare diseases.

AB - Brugada syndrome is a rare cardiac arrhythmia disorder, causally related to SCN5A mutations in around 20% of cases. Through a genome-wide association study of 312 individuals with Brugada syndrome and 1,115 controls, we detected 2 significant association signals at the SCN10A locus (rs10428132) and near the HEY2 gene (rs9388451). Independent replication confirmed both signals (meta-analyses: rs10428132, P = 1.0 × 10 -68; rs9388451, P = 5.1 × 10 -17) and identified one additional signal in SCN5A (at 3p21; rs11708996, P = 1.0 × 10 -14). The cumulative effect of the three loci on disease susceptibility was unexpectedly large (P trend = 6.1 × 10 -81). The association signals at SCN5A-SCN10A demonstrate that genetic polymorphisms modulating cardiac conduction can also influence susceptibility to cardiac arrhythmia. The implication of association with HEY2, supported by new evidence that Hey2 regulates cardiac electrical activity, shows that Brugada syndrome may originate from altered transcriptional programming during cardiac development. Altogether, our findings indicate that common genetic variation can have a strong impact on the predisposition to rare diseases.

U2 - 10.1038/ng.2712

DO - 10.1038/ng.2712

M3 - Letter

C2 - 23872634

SN - 1061-4036

VL - 45

SP - 1044

EP - 1049

JO - Nature: New biology

JF - Nature: New biology

IS - 9

ER -

Common variants at SCN5A-SCN10A and HEY2 are associated with Brugada syndrome, a rare disease with high risk of sudden cardiac death

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